Bristol-Myers Squibb Holdings Limited

AMIKIN INJECTION 100MG/2ML

Each vial contains amikacin sulphate equivalent to amikacin activity 100mg (100,000 international units) in 2 ml (50mg/ml).

Excipients: Each vial contains 2.94mg (0.13 mmol) sodium.

For full list of excipients, see section 6.1.

Solution for injection.

Clear colourless solution.

In the management of infections due to gram negative organisms sensitive to the anti-infective.

Consideration should be given to official guidance on the appropriate use of antibacterial agents

For most infections the intramuscular route is preferred, but in life-threatening infections, or in patients in whom intramuscular injection is not feasible the intravenous route may be used.

Intramuscular and intravenous administration

At the recommended dosage level, uncomplicated infections due to sensitive organisms should respond to therapy within 24 to 48 hours.

If clinical response does not occur within three to five days consideration should be given to alternative therapy.

Adults and children over 12 years:

The recommended intramuscular or intravenous dosage for adults and adolescents with normal renal function (creatinine clearance 50 ml/min) is 15 mg/kg/day which may be administered as a single daily dose or divided into 2 equal doses i.e. 7.5 mg/kg q 12 h. The total daily dose should not exceed 1.5 g. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing.

Children 4 weeks to 12 years:

The recommended intramuscular or intravenous (slow intravenous infusion) dose in children with normal renal function is 15-20 mg/kg/day which may be administered as 15-20 mg/kg, once a day; or as 7.5 mg/kg q 12 h. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing.

Neonates:

An initial loading dose of 10 mg/kg followed by 7.5 mg/kg q 12 h (see sections 4.4 and 5.2).

Premature infants:

The recommended dose in prematures is 7.5 mg/kg in every 12 hours (see sections 4.4 and 5.2).

Specific recommendation for intravenous administration

In paediatric patients the amount of diluents used will depend on the amount of amikacin tolerated by the patient. The solution should normally be infused over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion.

Elderly

Amikacin is excreted by the renal route, renal function should be assessed whenever possible and dosage adjusted as described under impaired renal function.

Life-threatening infections and/or those caused by Pseudomonas:

The adult dose may be increased to 500mg every eight hours but should neither exceed 1.5g/day nor be administered for a period longer than 10 days. A maximum total adult dose of 15g should not be exceeded.

Urinary tract infections: (other than pseudomonal infections):

7.5mg/kg/day in two equally divided doses (equivalent to 250mg b.i.d. in adults). As the activity of amikacin is enhanced by increasing the pH, a urinary alkalising agent may be administered concurrently.

Impaired renal function:

In patients with impaired renal function, the daily dose should be reduced and/or the intervals between doses increased to avoid accumulation of the drug. The critical serum creatinine concentration is 1.5mg/100ml.

Other routes of administration:

Amikin in concentrations of 0.25% may be used satisfactorily as an irrigating solution in abscess cavities, the pleural space and the peritoneum.

Hypersensitivity to any of the components of the product.

Use of amikacin intraperitoneally in young children or in patients under anaesthesia or muscle relaxing drugs.

Myasthenia gravis.

Patients should be well hydrated during amikacin therapy.

In patients with impaired renal function or diminished glomerular filtration, amikacin should be used cautiously. In such patients, renal function should be assessed by the usual methods prior to therapy and periodically during therapy. Daily doses should be reduced and/or the interval between doses lengthened in accordance with serum creatinine concentrations to avoid accumulation of abnormally high blood levels and to minimise the risk of ototoxicity.

Monitoring of drug levels should also be performed and trough concentrations > 4µg/ml should be avoided.

As with other aminoglycosides, ototoxicity and/or nephrotoxicity can result from the use of amikacin and are directly related to total dosage of drug, duration of therapy and degree of dehydration.

Monitoring of vestibular and auditory function should be carried out during and after treatment.

The use of amikacin in patients with a history of allergy to aminoglycosides or in patients who may have subclinical renal or eighth nerve damage induced by prior administration of nephrotoxic and/or ototoxic agents such as streptomycin, dihydrostreptomycin, gentamicin, tobramycin, kanamycin, bekanamycin, neomycin, polymyxin B, colistin, cephaloridine, or viomycin should be considered with caution, as toxicity may be additive.

In these patients amikacin should be used only if, in the opinion of the physician, therapeutic advantages outweigh the potential risks.

Paediatric use

Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.

The risk of ototoxicity is increased when amikacin is used in conjunction with rapidly acting diuretic drugs, particularly when the diuretic is administered intravenously. Such agents include frusemide and ethacrynic acid. Irreversible deafness may result.

The intraperitoneal use of amikacin is not recommended in patients under the influence of anaesthetics or muscle-relaxing drugs (including ether, halothane, d-tubocurarine, succinylcholine and decamethonium) as neuromuscular blockade and consequent respiratory depression may occur.

Indomethacin may increase the plasma concentration of amikacin in neonates.

In patients with severely impaired renal function, a reduction in activity of aminoglycosides may occur with concomitant use of penicillin-type drugs.

There are limited data on use of aminoglycosides in pregnancy. Aminoglycosides can cause foetal harm. Aminoglycosides cross the placenta and there have been reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although adverse effects on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. In reproduction toxicity studies in mice and rats no effects on fertility or foetal toxicity were reported. If amikacin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.

It is not known whether amikacin is excreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue therapy.

Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision (see section 4.4).

None stated.

Side effects include allergic reactions, tinnitus, headache, anaemia, purpura and increased levels of bilirubin occasionally. Ototoxicity and nephrotoxicity are the most significant problems. Urinary signs of renal irritation (albumin, casts and red or white blood cells), azotaemia and oliguria have been reported. There have been reports of retinal toxicity following intravitreal injection of amikacin.

The sodium bisulphite content of the product may rarely cause severe hypersensitivity reactions and bronchospasm.

In the event of overdosage or toxic reaction, peritoneal dialysis or haemodialysis will aid in the removal of amikacin from the blood.

Amikacin sulphate is an aminoglycoside antibiotic which is active against a broad spectrum of gram-negative organisms, including Pseudomonas spp, Escherichia coli, indole-positive and indole-negative Proteus spp., Klebsiella-Enterobacter-Serratia spp., Salmonella, Shigella, Minea-Herellae, Citrobacter freundii and Providencia spp..

Many strains of these gram-negative organisms resistant to gentamicin and tobramycin may show sensitivity to amikacin in vitro. The principal gram-positive organism sensitive to amikacin is Staphylococcus aureus, including methicillin-resistant strains. Amikacin has some activity against other gram-positive organisms including certain strains of Streptococcus pyogenes, Enterococci and Diplococcus pneumoniae.

Amikin is rapidly absorbed after intramuscular injection. Peak serum levels of approximately 11mg/l and 23mg/l are reached one hour after i.m. doses of 250mg and 500mg respectively. Levels 10 hours after injection are of the order of 0.3mg/l and 2.1mg/l respectively.

Twenty per cent or less is bound to serum protein and serum concentrations remain in the bactericidal range for sensitive organisms for 10 to 12 hours.

Amikin diffuses readily through extracellular fluids and is excreted in the urine unchanged, primarily by glomerular filtration. Half-life in individuals with normal renal functions is two to three hours.

Following intramuscular administration of a 250mg dose, about 65% is excreted in six hours and 91% within 24 hours. The urinary concentrations average 563 mg/l in the first 6 hours and 163 mg/l over 6 to 12 hours. Mean urine concentrations after a 500mg i.m. dose average 832 mg/l in the first six hours.

Single doses of 500mg administered to normal adults as an intravenous infusion over a period of 30 minutes produce a mean peak serum concentration of 38mg/l at the end of the infusion. Repeated infusions do not produce drug accumulation.

Amikin has been found in cerebrospinal fluid, pleural fluid, amniotic fluid and in the peritoneal cavity following parenteral administration.

Data from multiple daily dose trials show that spinal fluid levels in normal infants are approximately 10 to 20% of the serum concentrations and may reach 50% in meningitis.

Intramuscular and intravenous administration

In neonates and particularly in premature babies, the renal elimination of amikacin is reduced.

In a single study in newborns (1-6 days of post natal age) grouped according to birthweights (<2000, 2000-3000 and >3000g). Amikacin was administered intramuscularly and/or intravenously at a dose of 7.5 mg/kg. Clearance in neonates >3000 g was 0.84 ml/min/kg and terminal half-life was about 7 hours. In this group, the initial volume of distribution and volume of distribution at steady state was 0.3 ml/kg and 0.5 mg/kg, respectively. In the groups with lower birth weight clearance/kg was lower and half-life longer. Repeated dosing every 12 hours in all the above groups did not demonstrate accumulation after 5 days.

No further relevant information.

Sodium citrate

Sodium bisulphite (E222)

Sulphuric acid, for pH adjustment

Water for injection.

This medicinal product must not be mixed with any other medicinal products.

Unopened: 3 years.

To be used immediately after opening. Any remaining contents must be discarded.

Do not store above 25°C.

2 ml flint glass Type 1 vials with butyl rubber stopper and aluminium seal.

For single use only, discard any unused solution.

Bristol-Myers Squibb (Holdings) Ltd

t/a Bristol-Myers Pharmaceuticals

Swords

Co. Dublin

100 mg/2 ml: PA 48/4/4

15th July 1991 / 15th July 2006

January 2011

POM